Role of cten in the prostate cancer Prostate cancer is the most common malignancy in North American men. However, the genetic events associated with the malignant transformation of prostatic cells are largely unknown. Identification of new prostate specific genes could provide new markers and could be instrumental for development of new treatment modalities. Previously we have identified a new tensin family member, cten, whose expression is relatively restricted at the normal prostate gland. Our studies have demonstrated that cten is down-regulated in prostate cancer tissue and cells, is a target of caspase 3 and an effector during apoptosis, regulates cell migration, recruits a tumor suppressor, DLC-1, to focal adhesion sites and this interaction is critical for DLC- 1'tumor suppression activity. Interestingly, cten localizes not only to focal adhesions but to the nucleus as well, which suggests that cten may be a transducer molecule, possibly involved in nuclear events in addition to events at the cell surface. Furthermore, the cten gene is located on chromosome 17q21, a region often deleted in prostate cancer. These studies suggest that cten is a prostate-specific tumor suppressor gene whose disruption has repercussions in prostate cancer. Nonetheless, our very recent studies have indicated that although not normally expressed in other tissues such as the colon, cten is overexpressed in colon cancer and is involved in Wnt/Apc pathway, indicating that cten may possess an oncogenic activity in the colon. Therefore, cten may have dual functions that are tissue type specific. Based on our observations, we formulated the general hypothesis that cten is a prostate-specific tumor suppressor that plays important roles at the focal adhesions and in the nucleus;and that alteration of cten expression or function disrupts its normal actions and increases the risk for prostate cancer. In this renewal proposal we will continually investigate the tumor suppressor role of cten in the prostate and offer an explanation for the seemingly contradictory function of cten in colon cancer. There are three specific aims in this proposal to test our hypothesis: Aim 1. To determine the role of cten in regulating the tumor suppression activity of DLC-1 Aim 2. To dissect the role of cten in androgen receptor and Wnt signaling pathways, using in vitro systems Aim 3. To demonstrate the function of cten in prostate tumorigenesis, and create animal models for prostate cancer, using in vivo systems of conditionally knockout and compound mice The gene to be studied is a very unique molecule, a focal adhesion-nucleus protein that may regulate the DLC-1 tumor suppressor at focal adhesions and mediate a crosstalk between Wnt and androgen signaling in the nucleus. Verification of our hypothesis would indicate a possible role for cten as a novel therapy target for prostate cancer and maybe other cancer types as well. Our animal studies will reveal cten's in vivo function and provide better mouse prostate cancer models for studying prostate tumorigenesis and drug screening. Furthermore, cten loxP mice can be used to generate mouse models for other cancers, such as colon cancer.